Distinct epitope engagement confers differential activity of linvoseltamab vs teclistamab across BCMA mutations

B-cell maturation antigen (BCMA) is a well-established therapeutic target in multiple myeloma (MM). BCMA mutations have been identified among patients who relapsed after treatment with approved BCMA×CD3 bispecific antibodies (bsAbs; eg, teclistamab). BCMA mutations can impair bsAb binding and cytotoxic activity in vitro, suggesting an acquired resistance mechanism leading to clinical relapse. Linvoseltamab (human BCMA×CD3 bsAb) was recently approved for adults with heavily pretreated relapsed/refractory MM. Here, we compared the activity of linvoseltamab in the presence of cell lines expressing 4 BCMA mutations reported among patients treated with teclistamab: R27P, S30del, P34del (associated with resistance), and the germ line variant P33S (identified in a patient who relapsed but was not associated with resistance). Linvoseltamab retained binding to cells expressing BCMA R27P and S30del mutations and demonstrated robust Jurkat-nuclear factor of activated T cells (NFAT) reporter and primary T-cell activation, as well as targeted cytotoxicity against mutated BCMA that was comparable to wild-type BCMA. Conversely, teclistamab exhibited reduced binding and functional activity against these mutations. Both linvoseltamab and teclistamab showed impaired binding against P34del, consistent with diminished Jurkat-NFAT reporter, primary T-cell activation, and cytotoxicity. Both bsAbs retained activity against P33S. Cryogenic electron microscopy uncovered distinct binding orientations for linvoseltamab and teclistamab, consistent with the respective sensitivities to the studied BCMA mutations (ie, the selected residues contributed less to linvoseltamab binding than teclistamab binding, consistent with the broader activity of linvoseltamab across BCMA mutations). Although linvoseltamab may be less susceptible than teclistamab to resistance mechanisms involving R27P and S30del, the clinical relevance of our findings is to be established.